Exploring the reproductive exposure risks of phthalates and organophosphates in atmospheric particulate matter based on quantitative structure-activity relationships and network toxicology models

Abstract

Minimal study focused on the association between mixed pollutants in atmospheric particulate matter (PM_2.5) and their reproductive health risks. Utilizing a novel quantitative structure-activity relationship (QSAR) integrated machine learning algorithms, we evaluated the mixed reproductive health risks associated with phthalates (PAEs) and organophosphates (OPEs) exposure by assessing the affinities of these compounds binding to estrogen receptors (ER) and androgen receptors (AR). The mixed toxicity equivalent factor (TEF_mix) and mixed toxicity equivalent quantity (TEQ_mix) by the QSAR model were all smaller than the sum TEF and TEQ of individual PAEs and OPEs, which may be due to the antagonistic effect of PAEs and OPEs monomers on reproductive toxicity. Based on network toxicology approach, a total of 590 potential targets associated with PAEs and OPEs affecting sex hormones were initially identified, with an additional 50 core targets, including AR and ER. Di-2-ethylhexyl phthalate (DEHP), triphenyl phosphate (TPHP) and mono-(2-ethylhexyl) phthalate (MEHP) were key components to disrupt AR and ER signaling pathway, and was confirmed by molecular docking analysis. In addition to ER and AR, serine/threonine kinase 1 (AKT1) and heat shock protein 90α family A member 1 (HSP90AA1) might be key targets for reproductive toxicity, which have hardly mentioned before. Our study provided precious information on the mixed reproductive exposure risk of PAEs and OPEs in PM_2.5, and innovatively explored the potential mechanisms of PAEs and OPEs affecting human reproductive health using network toxicology.

Keywords: Atmospheric particulate matter; Network toxicology; Organophosphates; Phthalates; Quantitative structure-activity relationships.